ANTIMICROBIAL ACTIVITY OF SM-17466, A NOVEL CARBAPENEM ANTIBIOTIC WITH POTENT ACTIVITY AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS-AUREUS

The in vitro and in vivo antibacterial activities of SM-17466, a new 1 beta-methyl carbapenem, were evaluated against a wide range of clinic al bacterial isolates and compared with the activities of meropenem, i mipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of a ction against gram-positive bacteria, showing especially potent activi ty against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinica l isolates of methicillin-resistant Staphylococcus aureus were inhibit ed were 3.13, 50, 100, 1.56, and 3.13 mu g/ml, respectively. This acti vity of SM-17466 was almost equivalent to those of the antibiotics use d for the treatment of infections caused by this organism. SM-17466 al so showed bactericidal activity against methicillin-resistant S. aureu s. In contrast, SM-17466 was less active against gram-negative bacteri a, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highe st activity against Haemophilus influenzae and Bacteroides fragilis. S M-17466, at a 50% inhibitory concentration of less than 1 mu g/ml, bou nd to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillin-binding protein 2' in a methicillin-resistant strain (50% inhibitory concentration, 5.9 mu g /ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-1746 6 demonstrated excellent in vivo efficacy against methicillin-suscepti ble and -resistant S. aureus strains in a mouse peritoneal infection m odel: the efficacy of SM-17466 against methicillin-resistant strains w as equal to or one-third that of vancomycin. This activity was compara ble to the in vitro activity of SM-17466. The subcutaneous injection o f SM-17466 in mice revealed that the half-life of SM-17466 in serum wa s about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to h ydrolysis by swine renal dehydropeptidase I, to an extent comparable t o the resistance shown by meropenem.